Tumors are classified roughly into two categories, benign tumors and malignant tumors. A malignant tumor is characterized by that the tumor cells have, in addition to growth ability, the abilities of invasion into the surrounding tissue and metastasis to distant organs.
Often mistaken is that malignant tumor tissue consists of cancer cells only, but actually, as shown in FIG. 11, the tumor tissue consists of a mixture of cancer cells and cancer stroma. Cancer-associated fibroblasts (hereinafter sometimes abbreviated to CAFs) are known as typical cells that constitute cancer stroma. Cancer cells and CAFs stimulate each other to, for example, accelerate the growth of the cancer cells and allow the acquisition of metastatic ability and invasive ability by the cancer cells through epithelial mesenchymal transition (hereinafter sometimes abbreviated to EMT), forming a vicious circle in which the exacerbation of a tumor is promoted. That is, for example, humoral factors including cytokines and growth factors produced by cancer stromal cells stimulate cancer cells to promote the production of humoral factors from the cancer cells. Such stimulation by the cytokine etc. is known to further increase the production of humoral factors by the cancer stromal cells, leading to a vicious circle which promotes the exacerbation of the tumor. It has been revealed that CAFs show biological activities and a gene expression pattern different from those of normal fibroblasts (Non Patent Literature 1), and it is also known that CAFs play an important role in the above-mentioned vicious circle (Non Patent Literature 2). However, many of the properties are still unknown, and researches are proceeding today.
Many of antitumor agents are targeted at tumor cells only and show merely a limited effect on cancer stromal cells. Therefore, even when an antitumor agent is administered, humoral factors produced from cancer stromal cells stimulate the exacerbation of tumor cells and often allows the tumor cells to survive, which is a decisive factor for preventing the radical cure of a malignant tumor by use of an antitumor agent.
Natriuretic peptides include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These peptides are known to bind specifically to receptors having a guanylate cyclase domain and increase intracellular cGMP to express various physiological activities. The receptors have two types, namely natriuretic peptide receptor GC-A (also known as NPR-A) and natriuretic peptide receptor GC-B (also known as NPR-B), and it is known that ANP and BNP specifically bind to GC-A, and that CNP specifically binds to GC-B (Non Patent Literature 3).
ANP is a 28-amino acid peptide having a cyclic structure and is produced in and secreted from atrial cells. The peptide shows diuretic action in the kidney, and the action of relaxing and dilating vascular smooth muscles in blood vessels. In addition, ANP exerts antagonizing actions against the renin-angiotensin-aldosterone system and vasopressin. These actions comprehensively reduce the load on the heart through lowering the blood pressure, body fluid volume, etc. BNP is a 32-amino acid peptide having a cyclic structure. It was first found in the brain, but later research revealed that the peptide is produced and secreted mainly in ventricular cells rather than the brain. The peptide has similar actions to those of ANP. ANP and BNP specifically bind to GC-A and thereby promote production of cGMP to express the above-mentioned actions (Non Patent Literature 4). Indeed, the secretion of ANP is promoted with elevation of atrial filling pressure in congestive cardiac failure etc., and ANP alleviates the symptoms of congestive cardiac failure etc. via the above-mentioned actions. Human ANP (hANP) is clinically used as a therapeutic agent for acute cardiac failure in Japan. Also, the secretion of BNP is increased in cardiac failure patients, and BNP alleviates various symptoms associated with cardiac failure via the above-mentioned actions. Human BNP (hBNP) is approved as a therapeutic agent for acute cardiac failure in the United States etc.
CNP is a physiologically active peptide found in porcine brain, and it is known that mammals have in their bodies a 22-amino acid peptide CNP-22 and a 53-amino acid peptide CNP-53, which is an N-terminally elongated form of CNP-22. CNP was originally considered to function as a neuropeptide, but the following research revealed that the peptide also exists in peripheral tissues and plays an important role in the process of bone growth. It has been confirmed so far that CNP controls the differentiation and growth of chondrocytes mainly in the growth plate cartilage, and therefore CNP is a promising therapeutic agent for dwarfism including achondroplasia. Further, CNP is known to exert various physiological actions in locations other than the bone and the cartilage. Known actions of CNP on fibroblasts are as follows. CNP is expressed in cardiac fibroblasts and the expression level is increased as a result of stimulation by various inflammatory cytokines. CNP then suppresses DNA synthesis in cardiac fibroblasts and the fibroblasts' production of extracellular matrices, such as collagen, leading to suppression of cardiac fibrosis (Non Patent Literature 5). However, the action of CNP on malignant tumors and cancer stromal cells is unknown.
ANP and BNP are also known to have various physiological activities besides blood-pressure regulating actions including diuretic action, vasodilating action, etc. Regarding tumors, experimental reports have been submitted by Vesely et al. on the growth-suppressing effect of ANP on tumor cells (for example, Non Patent Literature 6 etc.). These reports indicate that, in addition to ANP, long acting natriuretic peptide, vessel dilator, kalliuretic peptide, etc., of which the amino acid sequences are not likely to contribute to binding to the natriuretic peptide receptor GC-A, have the same or stronger growth-suppressing activity on cancer cells as compared to the growth-suppressing activity of ANP whereas BNP does not have such a growth-suppressing activity. From this, it is considered that the growth-suppressing activity of ANP on tumor cells reported by Vesely et al. is not based on the agonist activity for GC-A. The actions of ANP and BNP related to the metastasis of cancer cells are still unknown even after the release of the reports by Vesely et al., and combinational use of ANP and/or BNP with CNP for treating a malignant tumor have not ever been reported.